The present invention relates to ester derivatives of 1,4-dihydropyridine-5-carboxylic acid with the general formula I, 
wherein
R=CN, NO2 or a xe2x80x94COORxe2x80x2 group, wherein Rxe2x80x2 represents a lower alkyl group;
R1=R6 or R4;
R2=lower alkoxy or R4;
R3=H or R4;
R4=a coumarin group with formula II; 
R5=H, lower alkyl, lower alkoxy, halogen, nitro, hydroxyl, or amino;
R6=H, lower alkyl, lower alkoxy, benzyloxy, cyano, nitro, carboxylic acid, optionally esterified with a lower alkanol, carboxamide, optionally substituted with 1-2 lower alkyl groups;
X a single bond, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, of xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)kxe2x80x94O, wherein n ranges from 1 to 6, m and k are each equal to or higher than 1 and the sum of m and k is smaller than or equal to 4; and
Y=phenylene, cycloalkylene, or a carbon atom substituted with 1 or 2 C1-C2-alkyl groups;
with the provisio that lower alkyl, lower alkoxy, lower alkanol, benzyloxy, phenylene and cycloalkylene may optionally be substituted with 1-3 groups chosen from hydroxyl, cyano, amino, halogen, in particular chlorine or fluorine, and nitro;
under the condition that at least 1 of the groups R1, R2 and R3 is the same as R4, as well as the N-oxide, stereoisomers and/or addition salts thereof with a pharmaceutically acceptable acid or base;
where the term xe2x80x9clower alkylxe2x80x9d represents an optionally branched alkyl group having 1 to 6 carbon atoms, preferably 1 or 2 carbon atoms; the term xe2x80x9clower alkanolxe2x80x9d represents a lower alkyl substituted with a hydroxyl group;
the term xe2x80x9clower alkoxyxe2x80x9d represents an optionally branched alkoxy group having 1 to 6 carbon atoms, preferably 1 or 2 carbon atoms; and
the term xe2x80x9ccycloalkylxe2x80x9d represents a cycloalkyl group having 3 to 8 carbon atoms.
It is remarked that more than 1 R1, R5, and R6 groups may be present.
Halogen is to be understood as a halogen atom chosen from the group consisting of fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
1. Field of the Invention (Technical Field)
The present invention relates to 1,4-dihydropyridine-5-carboxylic acid ester derivatives, method for the preparation thereof, and methods for the treatment of disease using such derivatives.
2. Background Art
The largest group of antiviral compounds known in the art are nucleoside-analogues. One significant disadvantage of nucleoside-analogues is that virus strains progressively develop resistance against them. Thus there is a need in the art for compounds having antiviral activity that are not nucleoside-analogues.
Coumarin derivatives have been described in the literature as having antiviral activity. For example, International Patent Application WO 92/18123 describes coumarin derivatives and closely related compounds such as alkoxycoumarin derivatives. It is indicated that these compounds are suitable for inhibiting the replication of retroviruses.
The present invention relates to three methods for preparing an ester derivative of 1,4-dihydropyridine-5-carboxylic acid.
The present invention is characterized in that either
A. i) a coumarin derivative of the formula III 
xe2x80x83is converted to an acetoacetate-ester having the general formula IV; 
ii) the acetoacetate-ester thus formed is reacted with a benzaldehyde having the formula V and an Rxe2x80x2-aminocrotonate, wherein Rxe2x80x2 is as defined before, yielding the desired ester derivative of 1,4-dihydropyridine-5-carboxylic acid; or,
B. i) a benzaldehyde derivative of the formula V, 
xe2x80x83wherein R1 and R6 are as defined before, is reacted with an R2-4-chloroacetoacetate, wherein R2 is as defined before, yielding a benzylidene of the formula VI; 
ii) the benzylidene formed in the previous step is reacted with an Rxe2x80x2-3-aminocrotonate, wherein Rxe2x80x2 is as defined before, yielding a 5-chloromethyl-1,4-dihydropyridine derivative of the formula VII; 
iii) the 5-chloromethyl-1,4-dihydropyridine derivative formed in step ii) is reacted under basic conditions with a coumarin derivative of the formula III, where X and R5 are as defined before, yielding the desired ester derivative of 1,4-dihydropyridine-5-carboxylic acid; or,
C. i) a coumarin derivative of the formula VIII; 
xe2x80x83where Z represents a leaving group and R5 is as defined before, while A represents xe2x80x94(CH2)nxe2x80x94, or xe2x80x94(CH2)mxe2x80x94Yxe2x80x94(CH2)kxe2x80x94 where n, m and k are as defined for X, are reacted under basic conditions with a benzaldehyde derivative of the formula V, where R1 and R6 have the meaning as defined before, yielding a Williamson ether of the formula IX; 
ii) the Williamson ether is reacted with an Rxe2x80x2-3-aminocrotonate derivative yielding the desired ester derivative of 1,4-dihydropyridine-5-carboxylic acid.
With respect to the method described under A, it is remarked that step A i) is conducted as described by Clemens R. J. et al. (J. Org. Chem. 50, pages 646-652, 1980). Step A. ii) concerns a Michael-addition reaction which is suitably performed in a polar solvent (such as methanol, ethanol or 2-propanol) and is described by Stout D. M. et al. (Chem. Rev. 82, pages 233-243, 1982).
With respect to the method described under B, it is remarked that the product (VI) obtained in step B i) does not have to be isolated, but can be condensated immediately in the subsequent step with the 3-aminocrotonate. The last step B. iii) concerns a preparation of a so-called Williamson ether ((Meerwein H., Methoden der Organischen Chemie (Houben Weyl) 6/3, p. 6-140).
Finally, with respect to the method described under C, it is remarked that step C i) concerns the preparation of a Williamson ether, which is performed under influence of a suitable base (such as potassium- or sodiumcarbonate, sodiumhydride, or triethylamine) in a polar inert solvent (for example methanol, acetone, dimethylformamide or dioxane). The second step C. ii) is again a Michael-addition, as described under step A. ii).
The present invention further relates to a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier or excipient.
Finally, the present invention relates to a pharmaceutical composition containing an ester derivative of 1,4-dihydropyridine-5-carboxylic acid according to the invention as the active compound, suitable for the treatment of a viral affliction, high blood pressure or glaucoma.
The viral afflictions may be such viral afflictions caused by:
1 Adenovirus type 2
2 Coxsackie virus B4
3 Cytomegalovirus (AD-169 strain; Davis strain)
4 Herpes simplex virus 1 (KOS; F; McIntyre; TK-B2006; TK-VMW1837; TK-Cheng C158/77; TK-Field C137/101)
5 Herpes simplex virus-2 (G; 196; Lyons)
6 HIV-1
7 HIV-2
8 Influenza virus A
9 Influenza virus B
10 Parainfluenza-3 virus
11 Polio virus-1
12 Reovirus
13 Respiratory syncytial virus
14 Semliki forest virus
15 Sindbis virus
16 Vaccinia virus
17 Varicella zoster virus (TK+ OKA strain; TK+ YS strain; TKxe2x88x92 07/1 strain; TKxe2x88x92 YS/R strain;
18 Vesicular stomatitus virus.